ABSTRACT Substance use disorders (SUDs) and depression are common among HIV-positive patients and lead to poor HIV treatment outcomes and increased mortality. Yet these disorders often go unrecognized and untreated, despite the availability of effective interventions. To enhance HIV care, this study examines the impact of self- administered tablet-based screening for SUD risk and depression using validated measures, with results integrated into the electronic health record and reviewed by behavioral health specialists (BHSs) embedded in primary care HIV clinics. Based on screening results, BHSs will initiate motivational interviewing (MI)- and cognitive behavioral therapy (CBT)-based clinical interventions. Using a hybrid study approach, we will evaluate both implementation and effectiveness of screening and intervention. Specifically, we will employ a stepped-wedge trial design, with a 12-month intervention phase implemented sequentially in the 3 largest HIV primary care clinics serving 4600 HIV-positive patients in Kaiser Permanente Northern California (KPNC), with a 12-month usual care period prior to implementation in each clinic functioning as an observational phase for comparison. This design, a variation of a cross-over RCT, allows for intervention refinement at each clinic and provides the opportunity to compare outcomes among patients before and after implementation. We will evaluate patient-level (e.g., demographics, HIV, SUD and depression severity) and provider-level (e.g., provider attitudes) factors affecting implementation and effectiveness, and will analyze cost effectiveness. The results of the study will provide insights regarding the implementation of evidence-based treatments for SUD and depression, such as: 1) How self-administered computerized SUD and depression screening and corresponding behavioral interventions can be effectively and efficiently implemented in HIV primary care clinics and sustained over time; 2) What patient and clinic characteristics influence screening and intervention rates; 3) To what extent implementation of screening and treatment impacts SUD and depression outcomes, as well as HIV outcomes, including retention in care, viral suppression and Veterans Aging Cohort Study index score, and 4) What are the barriers, facilitators and costs of implementation. The study setting is generalizable to other HIV clinics and health systems and will provide key data regarding the effective delivery of treatment options within primary care settings, and in coordination with SUD and psychiatry specialty care. Furthermore, the study addresses NIH-identified high priority HIV research topics since effective treatment of SUDs and/or depression would alleviate HIV treatment disparities for these individuals and reduce SUD- and depression- related medical comorbidity and mortality.